Alpha-substituted ketonitrone derivatives

ABSTRACT

α-Substituted ketonitrone derivatives containing substitutents selected from hydrogen, phenyl, substituted phenyl, naphythyl, furan, thiopen, imidazolylmethyl and triazolylmethyl are useful as intermediates for the preparation of biologically active isoxazolidine compounds.

BACKGROUND OF THE INVENTION

This invention relates to α-substituted ketonitrone derivatives usefulas intermediates for the preparation of antifungal isoxazolidinecompounds.

BRIEF SUMMARY OF THE INVENTION

In accordance with this invention there are provided compounds of theformula: ##STR1## wherein; R¹ is selected from 2-naphthyl, 2-furanyl,2-thienyl, phenyl, and substituted phenyl having one or more of the metaand para hydrogens substituted by halogen, lower alkoxy, lower alkyl orcombinations thereof,

R² is selected from hydrogen and phenyl, and X is selected from nitrogenand a methyn (CH═) group.

DETAILED DESCRIPTION OF THE INVENTION

The α-substituted ketonitrone derivatives (2) of the invention can beobtained as illustrated in the following diagram by reaction of anappropriately substituted ketone precursor (1) with N-methyl(orbenzyl)-hydroxylamine hydrochloride in absolute ethanol at room orelevated temperature in the presence of base, for example, alkali metalcarbonates, bicarbonates or acetates. Preferably, potassium carbonate orsodium acetate are used.

As used herein the terms "lower alkyl" and "lower alkoxy" refer tostraight and branched chain alkylene groups having 1 to 4 carbon atomsand halogen refers to chlorine, bromine, iodine and fluorine (preferablychlorine or fluorine). ##STR2##

The preparation of the compounds of the invention is further illustratedby the following examples. The appropriately substituted ketoneprecursors are prepared according to known procedures, for example,Godefroi et al., J. Medicinal Chem. 12 784 (1969), and Nardi et al., J.Medicinal Chem. 24 727 (1981).

EXAMPLE 1 2-(1H-Imidazol-1-yl)-N-methyl-1-phenylethanimine N-oxide

(2, R¹ =C₆ H₅, R² =H, X=CH)

Method A. A suspension of 18.70 g (0.100 mol) of2-(1H-imidazol-1-yl)acetophenone (1, R¹ =C₆ H₅, X=CH),N-methylhydroxylamine hydrochloride (9.78 g, 0.117 mol), and potassiumcarbonate (17.24 g, 0.125 mol) in 200 ml of absolute ethanol was stirredat 70°-75° C., under a nitrogen atmosphere, for 48 hours. The reactionmixture was then cooled to room temperature, filtered, and the solventremoved in vacuo, leaving a yellow oil which was dissolved in 400 ml ofethyl acetate and extracted with water (6×100 ml). The combined aqueouslayer was back-extracted with chloroform (8×100 ml). The combinedchloroform layer was dried over anhydrous sodium sulfate, filtered, andthe solvent removed in vacuo to give nitrone 2 (R¹ =C₆ H₅, R² =H, X=CH)as a white solid, 15.54 g (72%). An analytical sample was prepared byrecrystallization from ethyl acetate, mp 126°-128° C. Anal. Calcd forC₁₂ H₁₃ N₃ O: C, 66.96; H, 6.09; N, 19.52. Found: C, 66.74; H, 6.18; N,19.38.

Method B. A suspension of 5.58 g (0.0316 mol) of2-(1H-imidazol-1-yl)acetophenone (1, R¹ =C₆ H₅, X=CH),N-methylhydroxylamine hydrochloride (3.17 g, 0.0379 mol), and sodiumacetate (6.24 g, 0.0760 mol) in 50 ml of absolute ethanol was stirredfor 72 hours at room temperature, under a nitrogen atmosphere. Thesuspension was then filtered and the solvent removed in vacuo. Theresidual oily solid was taken up in chloroform, filtered and the solventremoved in vacuo. Crystallization from ethyl acetate gave 5.43 g (80%)of nitrone 2 (R¹ =C₆ H₅, R² =H, X=CH).

EXAMPLE 2 1-(4-Chlorophenyl)-2-(1H-imidazol-1-yl)-N-methylethanimineN-oxide

(2, R¹ =4-ClC₆ H₄, R² =H, X=CH)

Compound 2 (R¹ =4-ClC₆ H₄, R² =H, X=CH) was prepared by the proceduresdescribed in Example 1, Methods A and B by reacting2-(1H-imidazol-1-yl)-4'-chloroacetophenone (1, R¹ =4-ClC₆ H₄, X=CH) withN-methylhydroxylamine hydrochloride. Compound 2 (R¹ =4-ClC₆ H₄, R² =H,X=CH) has a melting point of 98°-102° C. (ethyl acetate). Anal. Calcdfor C₁₂ H₁₂ ClN₃ O: C, 57.72; H, 4.84; N, 16.83; Cl, 14.20. Found(method A prep): C, 57.53; H, 4.99; N, 16.87; Cl, 14.08.

EXAMPLE 3 1-(4-Fluorophenyl)-2-(1H-imidazol-1-yl)-N-methylethanimineN-oxide

(2, R¹ =4-FC₆ H₄, R² =H, X=CH)

Compound 2 (R¹ =4-FC₆ H₄, R² =H, X=CH) was prepared by the proceduresdescribed in Example 1, Methods A and B, by reacting2-(1H-imidazol-1-yl)-4'-fluoroacetophenone (1, R¹ =4-FC₆ H₄, X=CH) withN-methylhydroxylamine hydrochloride. Compound 2 (R¹ =4-FC₆ H₄, R² =H,X=CH) has a melting point of 131°-134° C. (ethyl acetate). Anal. Calcdfor C₁₂ H₁₂ FN₃ O: C, 61.79; H, 5.19, N, 18.02; F, 8.15. Found (method Aprep.): C, 62.02; H, 5.39; N, 17.96; F, 8.22.

EXAMPLE 4 2-(1H-Imidazol-1-yl)-1-(4-methoxyphenyl)-N-methylethanimineN-oxide

(2, R¹ =4-CH₃ OC₆ H₄, R² =H, X=CH)

Compound 2 (R¹ =4-CH₃ OC₆ H₄, R² =H, X=CH) was prepared by the proceduredescribed in Example 1, Method A, by reacting2-(1H-imidazol-1-yl)-4'-methoxyacetophenone (1, R¹ =4-CH₃ OC₆ H₄, X=CH)with N-methylhydroxylamine hydrochloride. Compound 2 (R¹ =4-CH₃ OC₆ H₄,R² =H, X=CH) has a melting point of 81°-84° C. (ethyl acetate-ether, 1:1by volume). Anal. Calcd for C₁₃ H₁₅ N₃ O₂ : C, 63.66; H, 6.16; N, 17.13.Found: C, 63.49; H, 6.28; N, 17.05.

EXAMPLE 5 2-(1H-Imidazol-1-yl)-1-(3-methoxyphenyl)-N-methylethanimineN-oxide

(2, R² =3-CH₃ O₆ H₄, R² =H, X=CH)

Compound 2 (R¹ =3-CH₃ OC₆ H₄, R² =H, X=CH) was prepared by the proceduredescribed in Example 1, Method A, by reacting2-(1H-imidazol-1-yl)-3'-methoxyacetophenone (1, R¹ =3-CH₃ OC₆ H₄, X=CH)with N-methylhydroxylamine hydrochloride. Compound 2 (R¹ =3-CH₃ OC₆ H₄,R² =H, X=CH) has a melting point of 87°-90° C. (ethyl acetate-hexane,1:1 by volume). Anal. Calcd for C₁₃ H₁₅ N₃ O₂ : C, 63.66; H, 6.16; N,17.13. Found: C, 63.70; H, 6.29; N, 17.08.

EXAMPLE 6 2-(1H-Imidazol-1-yl)-N-methyl-1-(3-methylphenyl)ethanimineN-oxide

(2, R¹ =3-CH₃ C₆ H₄, R² =H, X=CH)

Compound 2 (R¹ =3-CH₃ C₆ H₄, R² =H, X=CH) was prepared by the proceduredescribed in Example 1, Method B, by reacting2-(1H-imidazol-1-yl)-3'-methylacetophenone (1, R¹ =3-CH₃ C₆ H₄, X=CH)with N-methylhydroxylamine hydrochloride. Compound 2 (R¹ =3-CH₃ C₆ H₄,R² =H, X=CH) was obtained as a light yellow oil.

EXAMPLE 71-(4-Chloro-3-methylphenyl)-2-(1H-imidazol-1-yl)-N-methylethanimineN-oxide

(2, R¹ =4-Cl-3-CH₃ C₆ H₃, R² =H, X=CH) Compound 2 (R¹ =4-Cl-3-CH₃ C₆ H₃,R² =H, X=CH) was prepared by the procedure described in Example 1,Method A, by reacting2-(1H-imidazol-1-yl)-4'-chloro-3'-methylacetophenone (1, R¹ =4-Cl-3-CH₃C₆ H₃, X=CH) with N-methylhydroxyamine hydrochloride. Compound 2 (R¹=4-Cl-3-CH₃ C₆ H₅, R² =H, X=CH) was obtained as a light yellow oil.EXAMPLE 8

2-(1H-Imidazol-1-yl)-1-phenyl-N-(phenylmethyl)ethanimine N-oxide

(2, R¹ =R² =C₆ H₅, X=CH)

Compound 2 (R¹ =R² C₆ H₅, X=CH) was prepared by the procedure describedin Example 1, Method B, by reacting 2-(1H-imidazol-1-yl)acetophenone (1,R¹ =C₆ H₅, X=CH) with N-benzylhydroxylamine. Compound 2 (R¹ =R² =C₆ H₅,X=CH) was obtained as a light yellow oil.

EXAMPLE 91-(4-Fluorophenyl)-2-(1H-imidazol-1-yl)-N-(phenylmethyl)ethanimineN-oxide

(2, R¹ =4-FC₆ H₄, R² =C₆ H₅, X=CH)

Compound 2 (R¹ =4-FC₆ H₄, R² =C₆ H₅, X=CH) was prepared by the proceduredescribed in Example 1, Method B, by reacting2-(1H-imidazol-1-yl)-4'-fluoroacetophenone (1, R¹ =4-FC₆ H₄, X=CH) withN-benzylhydroxylamine. Compound 2 (R¹ =4-FC₆ H₄, R² =C₆ H₅, X=CH) wasobtained as a light yellow oil.

EXAMPLE 10 N-Methyl-1-phenyl-2-(1H-1,2,4-triazol-1-yl)ethanimine N-oxide

(2, R¹ =C₆ H₅, R² =H, X=N) was prepared by the procedure described inExample 1, Method A, by reacting 2-(1H-1,2,4-triazol-1-yl) acetophenone(1, R¹ =C₆ H₅, X=N) with N-methylhydroxylamine hydrochloride. Compound 2(R¹ =C₆ H₅, R² =H, X=N) has a melting point of 117°-119° C. (ethylacetate).

EXAMPLE 111-(4-Chlorophenyl)-N-methyl-2-(1H-1,2,4-triazol-1-yl)ethanimine N-oxide

(2, R¹ =4-ClC₆ H₄, R² =H, X=N)

Compound 2 (R¹ =4-ClC₆ H₄, R² =H, X=N) was prepared by the proceduredescribed in Example 1, Method A by reacting2-(1H-1,2,4-triazol-1-yl)-4'-chloroacetophenone (1, R¹ =4-ClC₆ H₄, X=N)with N-methylhydroxylamine hydrochloride. Compound 2 (R¹ =4-ClC₆ H₄, R²=H, X=N) has a melting point of 119°-121° C. (ethyl acetate). Anal.Calcd for C₁₁ H₁₁ ClN₄ O: C, 52.70; H, 4.42; N, 22.35; Cl, 14.14. Found:C, 52.65; H, 4.44; N, 22.37; Cl, 13.93.

EXAMPLE 121-(4-Methoxyphenyl)-N-methyl-2-(1H-1,2,4-triazol-1-yl)ethanimine N-oxide

(2, R¹ =4-CH₃ OC₆ H₄, R² =H, X=N)

Compound 2 (R¹ =4-CH₃ OC₆ H₄, R² =H, X=N) was prepared by the proceduredescribed in Example 1, Method A, by reacting2-(1H-1,2,4-triazol-1-yl)-4'-methoxyacetophenone (1, R¹ =4-CH₃ OC₆ H₄,X=N) with N-methylhydroxylamine hydrochloride. Compound 2 (R¹ =4-CH₃ OC₆H₄, R² =H, X=N) has a melting point of 128°-121° C. (ethyl acetate).Anal. Calcd for C₁₂ H₁₄ N₄ O: C, 58.53; H, 5.73; N, 22.75. Found: C,58.61; H, 5.76; N, 22.86.

EXAMPLE 131-(4-Fluorophenyl)-N-methyl-2-(1H-1,2,4-triazol-1-yl)ethanimine N-oxide

(2, R¹ =4-FC₆ H₄, R² =H, X=N)

Compound 2 (R¹ =4-FC₆ H₄, R² =H, X=N) was prepared by the proceduredescribed in Example 1, Method A, by reacting2-(1H-1,2,4-triazol-1-yl)-4'-fluoroacetophenone (1, R¹ =4-FC₆ H₄, X=N)with N-methylhydroxylamine hydrochloride. Compound 2 (R¹ =4-FC₆ H₄, R²=H, X=N) was obtained as a light yellow oil.

EXAMPLE 14N-Methyl-1-(3-methylphenyl)-2-(1H-1,2,4-triazol-1-yl)ethanimine N-oxide

(2, R¹ =3-CH₃ C₆ H₄, R² =H, X=N)

Compound 2 (R¹ =3-CH₃ C₆ H₄, R² =H=N) was prepared by the proceduredescribed in Example 1, Method B, by reacting2-(1H-1,2,4-triazol-1-yl)-3'-methylacetophenone (1, R¹ =3-CH₃ C₆ H₄,X=N) with N-methylhydroxylamine hydrochloride. Compound 2 (R¹ =3-CH₃ C₆H₄, R² =H, X=N) has a melting point of 98°-100° C. (ethyl acetate).

EXAMPLE 15 2-(1H-Imidazol-1-yl)-N-methyl-1-(2-naphthyl)ethanimineN-oxide

(2, R¹ =2-C₁₀ H₇, R² =H, X=CH)

Compound 2 (R¹ =2-C₁₀ H₇, R² =H, X=N) was prepared by the proceduresdescribed in Example 1, Method A and B, by reacting2-(1H-imidazol-1-yl)-1-(2-naphthyl)ethanone (1, R¹ =2-C₁₀ H₇, X=CH) withN-methylhydroxylamine hydrochloride. Compound 2 (R¹ =2-C₁₀ H₇, R² =H,X=CH) has a melting point of 112°-114° C. (ethyl acetate). Anal. Calcdfor C₁₆ H₁₅ N₃ O: C, 72.43; H, 5.70; N, 15.84. Found: (method A prep.)C, 72.14; H, 5.79; N, 15.74.

EXAMPLE 16 1-(2-Furanyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxide

(2, R¹ =2-C₄ H₃ O, R² =H, X=CH)

Compound 2 (R¹ =2-C₄ H₃ O, R² 32 H, X=CH) was prepared by the proceduredescribed in Example 1, Method B, by reacting1-(2-furanyl)-2-(1H-imidazol-1-yl)ethanone (1, R¹ =2-C₄ H₃ O, X=CH) withN-methylhydroxylamine hydrochloride. Compound 2 (R¹ =2-C₄ H₃ O, R² =H,X=CH) has a melting point of 130°-133° C. (ethyl acetate). Anal. Calcdfor C₁₀ H₁₁ N₃ O: C, 58.53, H, 5.40; N, 20.48. Found: C, 58.60; H, 5.47;N. 20.49.

EXAMPLE 17 2-(1H-Imidazol-1-yl)-N-methyl-1-(2-thienyl)ethanimine N-oxide

(2, R¹ =3-C₄ H₃ S, R² =H, X=CH)

Compound 2 (R¹ =2-C₄ H₃ S, R² =H, X=CH) was prepared by the proceduredescribed in Example 1, Method B, by reacting2-(1H-imidazol-1-yl)-1-(2-thienyl)ethanone (1, R¹ =2-C₄ H₃ S, X=CH) withN-methylhydroxylamine hydrochloride. Compound 2 (R¹ =2-C₄ H₃ S, R² =H,X=CH) has a melting point of 162°-164° C. (ethyl acetate).

The compounds of this invention are useful intermediates for thepreparation of substituted isoxazolidine derivatives having antifungalactivity. Examples of such derivatives are disclosed, for example, inour concurrently filed copending applications entitled "Substituted5-(Phenoxyalkyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines";"Substituted3,5-Diphenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidines" (U.S.Pat. No. 4,719,306), "3-(Substitutedphenyl)-3-(1H-imidazol-1-ylmethyl)-2-methyl-5-{[(substitutedphenyl)thio]methyl}isoxazolidine" Derivatives; and "3-(Substitutedphenyl)-3-(1H-1,2,4-triazol-1-yl)methyl-2-methyl-5-[(substitutedphenoxy)methyl]isoxazolidine Derivatives" whose disclosures areincorporated by reference herein.

The substituted isoxazolidines are prepared by reacting the compounds ofthe invention with an appropriate allyl benzene, allyl phenyl ether orallyl phenyl sulfide compound to provide the desired isoxazolidines. Forexample,5-(4-chlorophenoxymethyl)-3-phenyl-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidinecan be prepared by reacting the compound of Example 1 with4-chlorophenyl allyl ether in refluxing toluene in a nitrogen atmospherefor about 40 hours. Other compounds of the invention can be used toprepare corresponding isoxazolidines in a similar manner. Theisoxazolidines have been determined to have in vitro antifungal activityagainst yeast and systemic mycoses and dermatophytes as determined bybroth and agar testing techniques [(McGinnis, M. R., Laboratory Handbookof Medical Mycology, Academic Press, N.Y., N.Y. (1980)].

We claim:
 1. A compound of the formula: ##STR3## wherein; R¹ is selectedfrom 2-naphthyl, 2-furanyl, 2-thienyl, phenyl, and substituted phenylhaving one or more of the meta and para hydrogens substituted byhalogen, lower alkyl, lower alkoxy, or combinations thereof,R² isselected from hydrogen and phenyl, and X is a methyn group.
 2. Thecompound of claim 1 wherein R¹ is phenyl or substituted phenyl, R² ishydrogen, and X is methyn.
 3. The compound of claim 2 wherein thecompound is 2-(1H-imidazol-1-yl)-N-methyl-1-phenylethanimine N-oxide. 4.The compound of claim 2 wherein the compound is1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxide. 5.The compound of claim 2 wherein the compound is1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxide. 6.The compound of claim 2 wherein the compound is2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)-N-methylethanimine N-oxide. 7.The compound of claim 2 wherein the compound is2-(1H-imidazol-1-yl)-1-(3-methoxyphenyl)-N-methylethanimine N-oxide. 8.The compound of claim 2 wherein the compound is2-(1H-imidazol-1-yl)-N-methyl-1-(3-methylphenyl)ethanimine N-oxide. 9.The compound of claim 2 wherein the compound is1-(4-chloro-3-methylphenyl)-2-(1H-imidazol-1-yl)-N-methylethanimineN-oxide.
 10. The compound of claim 1 wherein R¹ is phenyl or substitutedphenyl, R₂ is phenyl, and X is methyn.
 11. The compound of claim 10wherein the compound is2-(1H-imidazol-1-yl)-1-phenyl-N-(phenylmethyl)ethanimine N-oxide. 12.The compound of claim 10 wherein the compound is1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)-N-(phenylmethyl)ethanimineN-oxide.
 13. The compound of claim 1 wherein R¹ is 2-naphthyl, R² ishydrogen and X is methyn.
 14. The compound of claim 13 wherein thecompound is 2-(1H-imidazol-1-yl)-N-methyl-1-(2-naphthyl)ethanimineN-oxide.
 15. The compound of claim 1 wherein R¹ is 2-furanyl, R² ishydrogen and X is methyn.
 16. The compound of claim 5 wherein thecompound is 1-(2-furanyl)-2-(1H-imidazol-1-yl)-N-methylethanimineN-oxide.
 17. The compound of claim 1 wherein R¹ is 2-thienyl, R² ishydrogen and X is methyn.
 18. The compound of claim 17 wherein thecompound is 2-(1H-imidazol-1-yl)-N-methyl-1-(2-thienyl)ethanimineN-oxide.